Clostridium bacteria are a spore forming family of Gram-positive anaerobes, including Clostridium(C) perfringens, C. tetani, C. botulinum and C. difficile. The Clostridium family of bacteria have been associated with a number of human maladies; in particular C. difficile has been shown to be the major causative agent for pseudomembraneous colitis and toxic megacolon as well as other antibiotic associated diarrheas (AAD).
C. difficile was first isolated in 1935 from intestinal flora of newborn infants (Hall et al., Am J Dis Child (1935) 49:390-402). In 1978, C. difficile was identified as the primary causative agent of pseudomembraneous colitis (now referred to as C. difficile associated diarrhea (CDAD)) (Bartlett et al., Gastroenterology (1978) 75:778-782), an inflammatory condition of the large intestine characterized by diarrhea that ranges in severity from mild to fulminant and is associated with the appearance of distinct raised plaques and neutrophil accumulation in the lumen of the intestinal lining. In general, these C. difficile related diarrheas result in about 10% to 30% mortality, especially in the elderly and in particular the elderly in hospital settings.
C. difficile has proven quite difficult to eradicate, especially in the hospital or healthcare setting (Loo et al., N. Engl. J. Med. (2005) 353:2442-2449; Thomas et al., J Antimicrob Chemother (2003) 51:1339-1350). In fact, whereas only 1-3% of healthy adults are carriers of C. difficile, hospitalization increases the risk of colonization to as high as 50% in a manner directly proportional to the length of hospitalization (Bartlett and Perl, N. Engl. J. Med. (2005) 353:2503-2505; Clabots et al., J. Infect. Dis., 166, 561-567, 1992; McFarland et al., N. Engl. J. Med., 320, 204-210, 1989). C. difficile infection is therefore a prevalent and growing problem within the healthcare industry.
There are few drugs that have shown promise in the treatment of CDAD. Presently, only vancomycin (125 mg four times a day for a period of seven to fourteen days) is approved by the FDA for treatment of CDAD. Metronidazole (250 mg three times a day for a period of seven to fourteen days) is also used extensively in clinical practice following early reports of its efficacy in CDAD (Teasley et al., Lancet (1983) 2:1043-1046; Wilcox and Spencer, J. Hosp. Infect. (1992) 22:85-92). However, recent studies have noted relatively high and growing incidence of treatment failure and relapse following metronidazole therapy (Pepin et al., Clin Infect Dis (2005) 40:1591-1597). Widespread vancomycin use in the treatment of CDAD (as well as other more common infections) has raised concerns about selection for vancomycin resistant strains of C. difficile and other bacteria. These concerns have led to proposals for first-line metronidazole use, with vancomycin being reserved for patients who are severely ill or have failed prior therapy. Bartlett et al., supra. Overall, options for the treatment of CDAD are limited, and there is a need in the industry for the development of new agents to address this prevalent and growing problem.
Amino acyl tRNA synthetases represent a promising platform for the development of new antibacterial agents with little cross-resistance to currently marketed antibiotics (Hurdle et al Antimicrob Agents Chemother. 2005 December; 49(12):4821-33). These synthetases play an essential role in protein synthesis by charging tRNA molecules with their corresponding amino acid so that the amino acid can be delivered to the ribosome for protein synthesis. In most bacteria, including C. difficile, a decrease in the ratio of charged to uncharged tRNA triggers a physiological reaction called the “stringent response.” The stringent response induces a down-regulation of the synthesis of rRNA and tRNA, thereby inhibiting protein synthesis and ultimately the attenuation of bacterial growth. As such, amino acyl tRNA synthetases represent a potentially new molecular target for antibacterial agents. The inhibitor mupirocin (an inhibitor of isoleucyl tRNA synthetase) was released as a topical antibiotic in the treatment of S. aureus and S. pyogenes infections. Mupirocin is produced by the organism Pseudomonas fluorescens, and is an antibacterial agent used as the active ingredient in the product Bactroban®, marketed by GlaxoSmithKline.
Against this backdrop the present invention has been developed.